To evaluate how passively acquired antiviral antibodies may modulate virus transmission and disease progression in human pediatric AIDS, we studied the potential of passive immunization with hyperimmune serum from macaques vaccinated against simian immunodeficiency virus (SIV) to prevent oral SIV infection or disease in newborn rhesus macaques. Two pre-exposure regimen and one post-exposure passive immunization regimen using subcutaneous inoculation of neonates with pooled, heat-inactivated SIV hyperimmune rhesus serum were compared with neonates receiving either pooled, normal rhesus serum or no serum. Three of four naive newborns and one newborn given pooled normal rhesus serum became infected after oral inoculation with pathogenic SIVmac251 and developed persistent high virus load in peripheral blood; three of the four infected animals had poor weight gain and were euthanatized at 10 to 13 weeks after inoculation with pathologic lesions diagnostic for SAIDS. One of the SIVmac251-infected control neonates developed intermittent plasma viremia and remained alive with no significant clinical disease for more than 10 months after inoculation. Three newborns were given SIV hyperimmune serum 3 weeks after oral inoculation with SIVmac251; all three neonates had high levels of cell-associated and cell-free viremia and poor weight gain at the time of passive immunization. No reduction in virus load or clinical improvement were observed in any of these three animals after passive immunization; all three were euthanatized with severe clinical disease and pathologic lesions diagnostic for SAIDS by 12 weeks after inoculation. In contrast, six newborn macaques given SIV hyperimmune serum prior to oral SIV inoculation did not become infected. These results indicate that passively acquired antiviral antibodies may prevent SIV infection of rhesus newborns by oral exposure, but may not reduce virus load or modulate disease in infant macaques that are already infected. *KEY* Pediatric simian AIDS, Mucosal virus transmission, Perimmune serum